Jennifer Spillane

Myasthenia and related disorders of the neuromuscular junction

Our understanding of transmission at the neuromuscular junction has increased greatly in recent years. We now recognise a wide variety of autoimmune and genetic diseases that affect this specialised synapse, causing muscle weakness and fatigue. These disorders greatly affect quality of life and rarely can be fatal. Myasthenia gravis is the most common disorder and is most commonly caused by autoantibodies targeting postsynaptic acetylcholine receptors. Antibodies to muscle-specific kinase (MuSK) are detected in a variable proportion of the remainder. Treatment is symptomatic and immunomodulatory. Lambert–Eaton myasthenic syndrome is caused by antibodies to presynaptic calcium channels, and approximately 50% of cases are paraneoplastic, most often related to small cell carcinoma of the lung. Botulism is an acquired disorder caused by neurotoxins produced by Clostridium botulinum, impairing acetylcholine release into the synaptic cleft. In addition, several rare congenital myasthenic syndromes have been identified, caused by inherited defects in presynaptic, synaptic basal lamina and postsynaptic proteins necessary for neuromuscular transmission. This review focuses on recent advances in the diagnosis and treatment of these disorders.

Myasthenia gravis--treatment of acute severe exacerbations in the intensive care unit results in a favourable long-term prognosis.

Acute severe exacerbations of myasthenia gravis (MG) are common in both early and late onset MG. We wished to examine the current management in the intensive care unit (ICU) of severe exacerbations of MG and to study the long‐term prognosis of MG following discharge from the ICU.

Clinically biphasic myasthenia gravis with both AChR and MuSK antibodies.

A humoral basis for myasthenia gravis was established in the 1970s following the identification of pathogenic antibodies directed against the post-synaptic acetylcholine receptor (AChR) [1]. These AChR antibodies are present in approximately 85 % of individuals with generalised MG (AChR-MG). Of the remaining ‘‘seronegative’’ individuals, between 40 and 70 % harbour antibodies against a muscle specific kinase (MuSK-MG) [2]. The targets of these two established pathogenic antibodies in MG are the acetylcholine receptor and muscle specific kinase, respectively. Whilst the AChR is pivotal for neuromuscular transmission, MuSK is considered to play an important role in the clustering of acetylcholine receptors and in synaptogenesis [3]. Emerging evidence suggests that the phenotype of MuSK-MG appears to be clinically distinct with individuals generally exhibiting prominent oculobulbar, neck and respiratory muscle involvement [4]. The occurrence of both AChR and MuSK antibodies in the same individual is highly unusual. To date, there have been four cases of patients harbouring both antibodies. One had concurrent Morvan’s syndrome [5]. The other three were initially AChR antibody positive at onset and subsequently became AChR antibody negative and MuSK antibody positive following thymectomy [6–8]. Here, we report the case of an individual who presented in adolescence with generalised MG with a bulbar predilection. Following thymectomy she went into complete remission for 15 years before re-presenting with severe oculobulbar, neck and respiratory muscle involvement. Her serum was positive for both AChR and MuSK antibodies post-thymectomy. We consider the clinical relevance and possible pathogenic mechanisms underlying this humoral phenomenon. The patient, who is of Bulgarian origin, first presented in 1973 at the age of 13 years with a subacute history of diplopia, swallowing difficulties and generalised weakness. A diagnosis of MG was made based on the clinical features and supportive EMG findings. She was treated symptomatically with Pyridostigmine. A few years later she underwent a thymectomy in Russia. The histology is unavailable. Following the thymectomy she remained in complete stable remission until 1999 when she experienced her first relapse consisting of diplopia, facial, bulbar and neck muscle weakness. She was treated with a course of oral Prednisolone to which she responded well. She remained in remission and off medication until 2006 when she experienced her second relapse which symptomatically was identical to her first. She had detectable AChR antibodies, and so MuSK antibody testing was not performed. She was initially treated with intravenous immunoglobulin (IVIG) to which she exhibited a partial response before slowly improving following a course of high dose oral Prednisolone. She was in remission and off medication for a further 5 years until her third relapse which was the most severe. In addition to diplopia in all directions of gaze, dysphagia, dysarthria, facial and neck weakness, she also complained of shortness of breath on exertion. Examination during her S. Rajakulendran (&) J. Spillane R. S. Howard National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK e-mail: s.rajakulendran@ion.ucl.ac.uk

Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels

Objective: To determine whether immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome (LEMS) decreases action potential–evoked synaptic vesicle exocytosis, and whether the effect is mediated by P/Q-type voltage-gated calcium channels (VGCCs). Methods: IgG was obtained from 4 patients with LEMS (3 males, 1 female), including 2 patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all 4 patients, and against N-type VGCCs in 2. We incubated neuronal cultures with LEMS IgG and determined the size of the total recycling pool of synaptic vesicles and the rate of action potential–evoked exocytosis using fluorescence imaging of the amphiphilic dye SynaptoRed C1. Pooled IgG from healthy volunteers was used as a control. We repeated the experiments on synapses lacking P/Q-type calcium channels from a Cacna1a knockout mouse to determine whether these channels account for the pathogenic effect of LEMS IgG. Results: LEMS IgG had no effect on the total recycling pool size but significantly reduced the rate of action potential–evoked synaptic exocytosis in wild-type neurons when compared with neurons treated with control IgG. In contrast, LEMS IgG had no effect on the rate of synaptic vesicle exocytosis in neurons lacking P/Q-type channels. Conclusions: These data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.

Myasthenia gravis and neuromyelitis opica: A causal link

Neuromyelitis Optica (NMO) and Myasthenia Gravis (MG) are rare antibody mediated disorders of the central nervous system (CNS) and neuromuscular junction (NMJ) respectively. Both diseases are predominantly mediated by IgG1 antibodies that activate complement. There have been increasing reports of patients who develop both disorders. Given the rarity of both diseases it would seem that these occurrences are not purely coincidental. There is heterogeneity between the cases described in the literature but common trends are observed in patients who develop both disorders. Most patients described are female. Typically the MG precedes the NMO and the majority of patients have undergone thymectomy. Generally, the symptoms of MG are mild but the NMO tends to follow a more aggressive clinical course. The pathogenesis of NMO in combination with MG is unknown, but thymectomy has been implicated in a subset of patients. We present the case of a female patient who developed NMO on a background of sero-positive MG and discuss the relevant literature.

Late recurrent thymoma in myasthenia gravis: a case series

Between 10% and 20% of patients with myasthenia gravis (MG) have a thymoma. Complete surgical removal forms the cornerstone of treatment regimes with adjuvant radiotherapy recommended in cases of incomplete resection. Thymomas are characterised by an indolent growth with good prognosis. However, recurrence is seen in 7–30% of patients.1 Myasthenic symptoms often remain after removal of a thymoma, with over 80% of the patients requiring continued immunosuppression.2 These patients continue to attend general neurology clinics and, therefore, it is necessary that neurologists are alert to the possibility of a thymoma recurrence. We describe five patients with MG who had undergone a thymectomy but developed late recurrence of thymoma. We undertook a review of the patient records from a dedicated MG clinic at the National Hospital for Neurology and Neurosurgery and identified cases of late recurrent thymoma. ‘Late’ was defined as a recurrence appearing at least 6 years after the initial resection. This interval was chosen based on a study showing that thymoma recurrence was usually observed within 6.25 years after the initial resection.3 Over many years, all of the patients were reviewed regularly by one of …

Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol.

Introduction: Slow channel congenital myasthenic syndrome is a dominant disorder characterized by prolonged acetylcholine receptor ion‐channel activation. Methods: Molecular genetic techniques, electrophysiology, and binding studies in human embryonic kidney (HEK) 293 cells determined mutant function and expression levels. Patient response to treatment was measured by quantitative myasthenic gravis and Medical Research Council grade strength scores. Results: We report an unusual case due to heteroallelic mutations in CHRNE. The slow channel mutation, p.εS278del, is accompanied by a severe low‐expression mutation, p.εR217L, on the second allele. Expression studies and cosegregation of p.εS278del with the disorder in the patients offspring demonstrate robust expression of the p.εS278del mutation. The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine. Conclusions: This case suggests that salbutamol, which is beneficial in some other congenital myasthenic syndromes, might also be considered in addition to fluoxetine in slow channel syndrome. Muscle Nerve, 2013

Diagnosis of skeletal muscle channelopathies

INTRODUCTION Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection. AREAS COVERED An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed. EXPERT OPINION A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants.

LAMBERT EATON MYASTHENIC SYNDROME ANTIBODIES DECREASE SYNAPTIC VESICLE EXOCYTOSIS IN NEURONAL CULTURES

Lambert Eaton Myasthenic Syndrome (LEMS) is an autoimmune disorder characterised by proximal muscle weakness and autonomic symptoms. Approximately 60% of cases are paraneoplastic. Antibodies to presynaptic voltage gated calcium channels of the P/Q–type are detected in 92% of LEMS patients. Presynaptic voltage gated calcium channels (VGCCs) both P/Q–and N–type, are the major trigger of action potential evoked release of neurotransmitters at peripheral and central synapses. Passive transfer of LEMS IgG to mice has been shown to reduce end plate potentials at the neuromuscular junction, suggesting that LEMS is caused by inhibition of neurotransmitter release. However, a direct effect of LEMS IgG on synaptic vesicular exocytosis has not been demonstrated. We tested the effects of LEMS IgG on synaptic vesicle exocytosis in dissociated hippocampal neuronal cultures. We compared the effects of chronic application (16 hours) of LEMS IgG from three separate LEMS patients and three control subjects on action potential–evoked vesicular release using fluorescence imaging of the styryl FM dye SynaptoRedC1 (SRC1). Recycling vesicles were labelled with SRC1 using high frequency field stimulation. Subsequent stimulation at 0.5 Hz triggered release of the trapped SRC1 dye from exocytosing vesicles, and the rate of fluorescence loss in individual synaptic boutons was used as a measure of the rate of vesicular exocytosis. The rate of action potential–evoked synaptic vesicle exocytosis was significantly decreased in LEMS treated neurones in comparison to neurones treated with control IgG. Spontaneous vesicular release was unaffected by LEMS IgG. Our results provide evidence that LEMS IgG can directly inhibit action potential–evoked synaptic vesicle release.

171 Myasthenic crisis in the intensive care unit: a 10-year review

Introduction The prognosis of autoimmune myasthenia gravis (MG) has improved with a reduction in mortality from 75% to a current rate of <5%. However, approximately 20% of MG patients will experience a myasthenic crisis requiring intensive care admission during the course of their illness. Aim To perform a 10 year audit on cases of myasthenic crisis admitted to a neurological intensive care unit. Methods Cases of myasthenic crisis were identified from the ICU register and case notes were retrospectively reviewed Results 38 patients were admitted in myasthenic crisis or were at risk of crisis. Five patients had multiple admissions. The average age at admission was 56.7. Twenty-five were female. Thirteen were male. Average disease duration at ICU admission was 2.6 years. Thirteen patients presented in crisis. 79% of patients were acetylcyholine receptor antibody positive. 13 % tested positive for MuSK antibodies and 7.8 % were seronegative. 31.5% of patients had a history of thymectomy. 58% of patients had a precipitating systemic infection. 50% required invasive mechanical ventilation. 80% received IVIG and 11% were treated with plasma exchange. The average duration of ICU stay was 11.5 days. There were four deaths all due to respiratory failure and sepsis. Conclusion MG continues to be a serious disease with a considerable morbidity and mortality. Management of myasthenic crisis requires specialised neuro-intensive care facilities.